A randomized clinical trial of hydroxymethylglutaryl-Coenzyme A reductase inhibition for Acute Lung Injury (The HARP study)

Rationale: There is no effective pharmacological treatment for acute lung injury (ALI). Statins are a potential new therapy because they modify many of the underlying processes important in ALI.

Objectives: To test whether simvastatin improves physiological and biological outcomes in ALI.

Methods: We conducted a randomized, double-blinded, placebo-controlled trial in patients with ALI. Patients received 80 mg simvastatin or placebo until cessation of mechanical ventilation or up to 14 days. Extravascular lung water was measured using thermodilution. Measures of pulmonary and nonpulmonary organ function were assessed daily. Pulmonary and systemic inflammation was assessed by bronchoalveolar lavage fluid and plasma cytokines. Systemic inflammation was also measured by plasma C-reactive protein.

Measurements and Main Results: Sixty patients were recruited. Baseline characteristics, including demographics and severity of illness scores, were similar in both groups. At Day 7, there was no difference in extravascular lung water. By Day 14, the simvastatin-treated group had improvements in nonpulmonary organ dysfunction. Oxygenation and respiratory mechanics improved, although these parameters failed to reach statistical significance. Intensive care unit mortality was 30% in both groups. Simvastatin was well tolerated, with no increase in adverse events. Simvastatin decreased bronchoalveolar lavage IL-8 by 2.5-fold (P = 0.04). Plasma C-reactive protein decreased in both groups but failed to achieve significance in the placebo-treated group.

Conclusions: Treatment with simvastatin appears to be safe and may be associated with an improvement in organ dysfunction in ALI. These clinical effects may be mediated by a reduction in pulmonary and systemic inflammation.

(223)Ra and other bone-targeting radiopharmaceuticals-the translation of radiation biology into clinical practice

Osseous metastases are a source of significant morbidity for patients with a variety of cancers. Radiotherapy is well established as an effective means of palliating symptoms associated with such metastases. The role of external beam radiotherapy is limited where sites of metastases are numerous and widespread. Low linear energy transfer (LET) radionuclides have been utilized to allow targeted delivery of radiotherapy to disparate sites of disease, with evidence of palliative benefit. More recently, the bone targeting, high LET radionuclide (223)Ra has been shown to not only have a palliative effect but also a survival prolonging effect in metastatic, castration-resistant prostate cancer with bone metastases. This article reviews the different radionuclide-based approaches for targeting bone metastases, with an emphasis on (223)Ra, and key elements of the underlying radiobiology of these that will impact their clinical effectiveness. Consideration is given to the remaining unknowns of both the basic radiobiological and applied clinical effects of (223)Ra as targets for future research.

Removing the threat of diclofenac to critically endangered Asian vultures

Veterinary use of the nonsteroidal anti-inflammatory (NSAID) drug diclofenac in South Asia has resulted in the collapse of populations of three vulture species of the genus Gyps to the most severe category of global extinction risk. Vultures are exposed to diclofenac when scavenging on livestock treated with the drug shortly before death. Diclofenac causes kidney damage, increased serum uric acid concentrations, visceral gout, and death. Concern about this issue led the Indian Government to announce its intention to ban the veterinary use of diclofenac by September 2005. Implementation of a ban is still in progress late in 2005, and to facilitate this we sought potential alternative NSAIDs by obtaining information from captive bird collections worldwide. We found that the NSAID meloxicam had been administered to 35 captive Gyps vultures with no apparent ill effects. We then undertook a phased programme of safety testing of meloxicam on the African white-backed vulture Gyps africanus, which we had previously established to be as susceptible to diclofenac poisoning as the endangered Asian Gyps vultures. We estimated the likely maximum level of exposure (MLE) of wild vultures and dosed birds by gavage (oral administration) with increasing quantities of the drug until the likely MLE was exceeded in a sample of 40 G. africanus. Subsequently, six G. africanus were fed tissues from cattle which had been treated with a higher than standard veterinary course of meloxicam prior to death. In the final phase, ten Asian vultures of two of the endangered species (Gyps bengalensis, Gyps indicus) were dosed with meloxicam by gavage; five of them at more than the likely MLE dosage. All meloxicam-treated birds survived all treatments, and none suffered any obvious clinical effects. Serum uric acid concentrations remained within the normal limits throughout, and were significantly lower than those from birds treated with diclofenac in other studies. We conclude that meloxicam is of low toxicity to Gyps vultures and that its use in place of diclofenac would reduce vulture mortality substantially in the Indian subcontinent. Meloxicam is already available for veterinary use in India.

Behavior, pain perception, and the extremely low-birth weight survivor

This article explores the literature concerning responses to pain of both premature and term-born newborn infants, the evidence for short-term and long-term effects of pain, and behavioral sequelae in individuals who have experienced repeated early pain in neonatal life as they mature. There is no doubt that pain causes stress in babies and this in turn may adversely affect long-term neurodevelopmental outcome. Although there are methods for assessing dimensions of acute reactivity to pain in an experimental setting, there are no very good measures available at the present time that can be used clinically. In the clinical setting repeated or chronic pain is more likely the norm rather than infrequent discrete noxious stimuli of the sort that can be readily studied. The wind-up phenomenon suggests that, exposed to a cascade of procedures as happens with clustering of care in the clinical setting in an attempt to provide periods of rest for stressed babies, an infant may in fact perceive procedures that are not normally viewed as noxious, as pain. Pain exposure during lifesaving intensive medical care of ELBW neonates may also affect subsequent reactivity to pain in the neonatal period, but behavioral differences are probably not likely to be clinically significant in the long term. Prolonged and repeated untreated pain in the newborn period, however, may produce a relatively permanent shift in basal autonomic arousal related to prior NICU pain experience, which may have long-term sequelae. In the long run, the most significant clinical effects of early pain exposure may be on neurodevelopment, contributing to later attention, learning, and behavior problems in these vulnerable children. Although there is considerable evidence to support a variety of adverse effects of early pain, there is less information about the long-term effects of opiates and benzodiazepines on the developing central nervous system. Current evidence reviewed suggests that judicious use of morphine for adjustment to mechanical ventilation may ameliorate the altered autonomic response. It may be very important, however, to distinguish stress from pain. Animal evidence suggests that the neonatal brain is affected differently when exposed to morphine administered in the absence of pain than in the presence of pain. Pain control may be important for many reasons but overuse of morphine or benzodiazepines may have undesirable long-term effects. This is a rapidly evolving area of knowledge of clear relevance to clinical management likely to affect long-term outcomes of high-risk children.

Non-invasive ventilation for cystic fibrosis.

Non-invasive ventilation may be a means to temporarily reverse or slow the progression of respiratory failure in cystic fibrosis. To compare the effect of non-invasive ventilation versus no non-invasive ventilation in people with cystic fibrosis. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches, handsearching relevant journals and abstract books of conference proceedings. We searched the reference lists of each trial for additional publications possibly containing other trials.Most recent search: 22 February 2013. Randomised controlled trials comparing a form of pressure preset or volume preset non-invasive ventilation to no non-invasive ventilation in people with acute or chronic respiratory failure in cystic fibrosis. Three reviewers independently assessed trials for inclusion criteria and methodological quality, and extracted data. Fifteen trials were identified; seven trials met the inclusion criteria with a total of 106 participants. Six trials evaluated single treatment sessions and one evaluated a six-week intervention.Four trials (79 participants) evaluated non-invasive ventilation for airway clearance compared with an alternative chest physiotherapy method and showed that airway clearance may be easier with non-invasive ventilation and people with cystic fibrosis may prefer it. We were unable to find any evidence that NIV increases sputum expectoration, but it did improve some lung function parameters.Three trials (27 participants) evaluated non-invasive ventilation for overnight ventilatory support, measuring lung function, validated quality of life scores and nocturnal transcutaneous carbon dioxide. Due to the small numbers of participants and statistical issues, there were discrepancies in the results between the RevMan and the original trial analyses. No clear differences were found between non-invasive ventilation compared with oxygen or room air except for exercise performance, which significantly improved with non-invasive ventilation compared to room air over six weeks. Non-invasive ventilation may be a useful adjunct to other airway clearance techniques, particularly in people with cystic fibrosis who have difficulty expectorating sputum. Non-invasive ventilation, used in addition to oxygen, may improve gas exchange during sleep to a greater extent than oxygen therapy alone in moderate to severe disease. These benefits of non-invasive ventilation have largely been demonstrated in single treatment sessions with small numbers of participants. The impact of this therapy on pulmonary exacerbations and disease progression remain unclear. There is a need for long-term randomised controlled trials which are adequately powered to determine the clinical effects of non-invasive ventilation in cystic fibrosis airway clearance and exercise.

COMPARISON OF THE GROWTH INHIBITORY AND BACTERIOCIDAL EFFECTS OF TAUROLIDINE AND TAURULTAM ON A CLINICAL ISOLATE OF ESCHERICHIA-COLI

To investigate the mode of action of Taurolin, an antimicrobial preparation, the growth inhibitory and bacteriocidal effects of taurolidine and taurultam solutions on Escherichia coli isolated from a diagnosed urinary tract infection were examined at 37-degrees-C. The inhibitory effects of taurolidine solutions were observed to be greater than those of taurultam solutions at comparative concentrations; however, the presence of sublethal concentrations of formaldehyde (methylene glycol) associated with taurolidine was sufficient to account for this. The bacteriocidal activity of taurolidine (2.0% w/v) was greater than that of taurultam (4.5% w/v). Both compounds produced biphasic death rates with dissimilar initial slopes, suggested to be due to the presence of formaldehyde in taurolidine solutions. These observations indicate that the growth inhibitory and bacteriocidal effects of Taurolin solutions are primarily due to taurultam, however, the presence of sublethal concentrations of formaldehyde is significant in the expression of this activity.

Nanoencapsulation of ABT-737 and camptothecin enhances their clinical potential through synergistic antitumor effects and reduction of systemic toxicity

The simultaneous delivery of multiple cancer drugs in combination therapies to achieve optimal therapeutic effects in patients can be challenging. This study investigated whether co-encapsulation of the BH3-mimetic ABT-737 and the topoisomerase I inhibitor camptothecin (CPT) in PEGylated polymeric nanoparticles (NPs) was a viable strategy for overcoming their clinical limitations and to deliver both compounds at optimal ratios. We found that thrombocytopenia induced by exposure to ABT-737 was diminished through its encapsulation in NPs. Similarly, CPT-associated leukopenia and gastrointestinal toxicity were reduced compared with the administration of free CPT. In addition to the reduction of dose-limiting side effects, the co-encapsulation of both anticancer compounds in a single NP produced synergistic induction of apoptosis in both in vitro and in vivo colorectal cancer models. This strategy may widen the therapeutic window of these and other drugs and may enhance the clinical efficacy of synergistic drug combinations.

Communicating clinical trial outcomes: Effects of presentation method on physicians’ evaluations of new treatments

Physicians expect a treatment to be more effective when its clinical outcomes are described as relative rather than as absolute risk reductions. We examined whether effects of presentation method (relative vs. absolute risk reduction)
remain when physicians are provided the baseline risk information, a vital piece of statistical information omitted in previous studies. Using a between-subjects design, ninety five physicians were presented the risk reduction associated
with a fictitious treatment for hypertension either as an absolute risk reduction or as a relative risk reduction, with or without including baseline risk information. Physicians reported that the treatment would be more effective and that they would be more willing to prescribe it when its risk reduction was presented to them in relative rather than in absolute terms. The relative risk reduction was perceived as more effective than absolute risk reduction even when the baseline risk information was explicitly reported. We recommend that information about absolute risk reduction be made available to physicians in the reporting of clinical outcomes. Moreover, health professionals should be cognizant of the potential biasing effects of risk information presented in relative risk terms

Cognitive inhibition and interference in dissociative indentity disorder: the effects of anxiety on specific executive functions:The effects of anxiety on specific executive functions

Using an experimentally based, computer-presented task, this study assessed cognitive inhibition and interference in individuals from the dissociative identity disorder (DID; n=12), generalized anxiety disorder (GAD; n=12) and non-clinical (n=12) populations. Participants were assessed in a neutral and emotionally negative (anxiety provoking) context, manipulated by experimental instructions and word stimuli. The DID sample displayed effective cognitive inhibition in the neutral but not the anxious context. The GAD sample displayed the opposite findings. However, the interaction between group and context failed to reach significance. There was no indication of an attentional bias to non-schema specific negative words in any sample. Results are discussed in terms of the potential benefit of weakened cognitive inhibition during anxious arousal in dissociative individuals.

Differential effects of the CCKA receptor ligands PD-140, 548 and A-71623 on latent inhibition in the rat.

Latent inhibition (LI) is a behavioural paradigm in which repeated exposure to a stimulus without consequence inhibits the formation of any new associations with that stimulus. To the extent that LI reflects a process of learning to ignore irrelevant stimuli, disrupted LI has been suggested as an animal model for the attentional deficits observed in schizophrenia. The antipsychotic potential of cholecystokinin (CCK) stems from its colocalization with dopamine (DA) in the mesolimbic pathway, where it demonstrates both excitatory and inhibitory effects on dopaminergic activity. This may be explained by mediation through different receptor subtypes. A variety of hypotheses has emerged regarding the potential clinical application of subtype-selective CCK-based drugs. The present experiments examined the effects on LI of two selective CCKA ligands: PD-140,548 (a CCKA antagonist, Experiment 1: 0.001, 0.01, and 0.1 mg/kg) and A-71623 (a CCKA agonist, Experiment 2: 0.02, 0.05, and 0.1 mg/kg). In both experiments, the effects of haloperidol (0.1 mg/kg) were also investigated. Animals receiving 0.1 mg/kg of haloperidol or 0.001 or 0.1 mg/kg (but not 0.01 mg/kg) of PD-140,548 treated the preexposed stimulus as irrelevant after a low number of preexposures. In contrast, no facilitatory effect on LI was detectable at any of the A-71623 doses. The finding that A-71623 failed to enhance LI indicates that it is unlikely that this compound would have any antipsychotic effect within the clinical setting. Considering the facilitatory effect exerted by PD-140,548 on LI, it is probable that the inhibition of CCK activity might prove a more promising strategy for the pharmacological treatment of schizophrenia.

Distinctive effects of G-CSF, GM-CSF and TNFalpha on neutrophil apoptosis in systemic lupus erythematosus.

OBJECTIVE: To investigate the influence of culture with G-CSF GM-CSF and TNFalpha on neutrophil apoptosis, comparing neutrophils from SLE patients with rheumatoid arthritis (RA) patients and healthy control subjects. METHODS: Neutrophils were isolated from SLE (n= 10), RA (n= 10) and healthy control subjects (n= 10), and cultured with two different concentrations of G-CSF, GM-CSF and TNFalpha. Proportion of apoptotic neutrophils at T=0, T=2hrs and T=24hrs was measured using FITC-labelled annexinV and flow cytometry. RESULTS: Significantly more neutrophils were apoptotic at T=0 in the SLE subjects than in the other groups (median, range--Control 3.5% (0.3-7.9) SLE 9.5% (2.9-29.1) RA 3.0% (0.4-23.0) p